Apoptosis is critical in lymphocyte proliferation and cytotoxicity, as well as maintenance of peripheral tolerance. Studies have indicated that lack of functional Fas antigen (CD95) or its ligand can results in a potentially fatal autoimmune disease in mice. The role of Fas/Fas ligand in human lymphocytes, however, remains largely unelucidated. Based on the characterization of murine Fas function, we propose that the expression and function of human Fas can be regulated by cytokines and/or costimulatory molecules. The hypothesis to be tested specifically in this proposal is that the regulation of human Fas antigen expression and function by a spectrum & immunoregulatory cytokines, such as IL-12 and IL-10, and/or costimulatory molecules, such as CD28 and CD3, can determine the ultimate sensitivity of activated human lymphocytes to anti-Fas mediated apoptosis as well as of the contribution of Fas/Fas ligand to human lymphocyte-mediated-cytotoxicity. Specifically, we will (1) examine the role of cytokines and costimulatory signals in the expression and regulation of Fas and its ligand, and the subsequent effect on activation induced apoptosis of human lymphocytes, and (2) elucidate the contribution of Fas/Fas ligand in human lymphocyte mediated cytotoxicity. Understanding the role of Fas antigen in apoptosis and cytotoxicity of human lymphocytes will offer significant insight into the regulatory mechanisms controlling lymphoproliferation and, possibly, targets for therapy of human autoimmune disease and cancer.